The invention relates to azole derivatives and methods for making the same and more specifically to carboxylic acid and phosphate ester derivatives of fluconzaole and voriconazole and methods for making the same. This invention further relates to use of the voriconazole and fluconazole derivatives as anti-fungal agents.
In recent years fungal infections have emerged as a major cause of disease and mortality, in part as a consequence of the increase in acquired immunodeficiency syndrome (AIDS), the greater use of immunosuppressive drugs, the long term use of corticosteroids, and even the indiscriminate use of antibiotics. Fridkin et al., Clin. Microbiol Rev. 1996, 9, 499; Larocco, M. T. et al., Clin. Microbiol. Rev. 1997, 10, 277; Patel et al., C. V. Clin. Microbiol. Rev. 1997, 10, 86. There are effective antifungal agents in the market, but each drug carries several drawbacks. The presently marketed antifungal drugs are either highly toxic (e.g., amphotericin B, A MB) or are becoming ineffective due to appearance of resistant strains (e.g. flucytosine and azoles). AMB remains the “gold standard” drug for life-threatening fungal infections, but its use is limited due to its severe toxicity and the inconvenience of intravenous dosing. Perfect, J. R. et al, Drug Safety 1992, 7, 323; Sabra, R. et al., Drug Safety 1990, 5, 94. Fluconazole (FLC) is an orally effective azole-based antifungal drug with low toxicity, (Kauffman, C. A. et al., Drugs 1997, 53, 539) but it has a limited antifungal spectrum and is not fungicidal. Although FLC shows efficacy against Candida albicans and C. neoformans, it is not very effective against Aspergillus niger (Schmitt, H. J. et al, Chemotherapy 1992, 38, 118; Zakula, D.; Capobianco, J. O. et al., Antimicrobial Chemotherapy 1997, 39, 261) and Aspergillus fumigatus. Tsukuda, T. et al., Bioorg Med. Chem. Lett. 1998, 8, 1819. In addition, extensive use of FLC has increased the number of F LC-resistant C. albicans isolates. Rex, J. H. et al., Antimicrob. Agents Chemother. 1995, 39, 1.
Therefore, toxicity concerns, limited spectrum, and the emergence of fungi resistant to currently available agents have created a need for antifungal agents and in particular antifungal agents effective against life-threatening systemic mycoses caused by C. neoformans, Aspergillus species, and Candida species.